Ocular formulations for drug-delivery and protection of the anterior segment of the eye
A kind of ophthalmic preparation and preparation technology, which is applied in the direction of drug delivery, drug combination, medical preparation of non-active ingredients, etc., and can solve the problems of limited permeability of the cornea and conjunctival barrier
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Embodiment 1
[0510] Primary Pharmacodynamics
[0511] In Vitro Potency Pharmacology of Compound-I . Compound-I potently inhibits the tyrosine kinase activity of vascular endothelial growth factor receptor-2 (VEGF-2) as well as a select subset of other pro-angiogenic RTKs during various in vitro assays. Specifically, Compound-I compounds blocked VEGF-stimulated VEGFR-2 phosphorylation in whole cells and proliferation of cultured endothelial cells. Compound-I was treated with 50% inhibitory concentrations (IC of 10.55 nM (6 ng / mL) and 8.79 nM (5 ng / mL) 50 ) to inhibit the recombinant tyrosine kinase activity of VEGFR-2 and FGFR-2; and with IC 50 = 5.27 nM (3 ng / mL) inhibits autophosphorylation of VEGFR-2 in intact cells. This inhibition is selective relative to many other tyrosine kinases, for example, VEGFR-2IC 50 About 1 / 500 and 1 / 1000 of the epidermal growth factor receptor (EGFR) and insulin receptor (IR) tyrosine kinases, respectively (see Table 2).
[0512] When using a 10-po...
Embodiment 2
[0519] Sodium Phosphate Based Gel Drops
[0520] The ophthalmic effects of Compound-I in sodium phosphate based formulations (listed in Table 6) are derived from the self-gelling properties of the API in buffers such as sodium phosphate. A self-forming thixotropic gel of Compound-I formed spontaneously from a clear solution was formed by increasing the API concentration in sodium phosphate. This gel appears initially clear, and then exhibits an increase in consistency / viscosity at higher API concentrations, and gradually becomes more opaque, ie turbid. Insoluble microparticles of Compound-I were also observed in the gel once the API concentration in phosphate buffer reached supersaturation.
[0521] Applying a gel of increased viscosity to the surface of the eye increases corneal dwell time. Increase the corneal residence time to facilitate the absorption of ophthalmic drugs. As a result, viscous gels have increased intraocular drug concentrations compared to non-viscous ...
Embodiment 3
[0525] Tromethamine-based suspensions
[0526] Compound-I (about 1 mg / mL to about 10 mg / mL) forms a suspension in the tromethamine-based formulation. Suspensions of Compound-I in tromethamine-based formulations had >95% active drug substance in insoluble form. This feature is distinguished from the soluble or semi-soluble state of Compound-1 in gel drops (gel drops (gels) are not in a fully soluble state when the concentration of active agent is increased) or in cyclodextrin-based formulations . The trometamol-based formulation of Compound-I showed increased turbidity with increasing active agent concentration. Application of topical drops of Compound-I suspension to the eye, which is a combination of soluble and insoluble active agent components, is expected to provide unique benefits with regard to safety / tolerability and efficacy.
[0527] A trometamol-based suspension of Compound-I was administered to Dutch striped rabbits for 4 or 5 consecutive days, with three doses...
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